Middle ear (ME) pressure regulation requires that Eustachian tube (ET) openings supply sufficient quantities of gases to balance the net loss due to transmucosal gas exchange with blood. Dysregulation causes ME under- pressures, mucosal inflammation and otitis media with effusion (OME). Disruption of the balance supply-demand relationship can result from a decreased volume of gas exchanged during ET dilations, an increased rate of transmucosal gas exchange, or both A knowledge of the mechanisms that control pressure regulation and of the conditions that disrupt normal function is fundamental to developing rationale preention or treatment strategies for OME. Recent studies conducted by us provided convincing support for the hydrops ex vacuo theory of disease pathogenesis and also showed that ET function can be up-regulated by preconditions to ME pathology. Free parameters of a mathematical model of ME pressure regulation were estimated in the monkey. Using those estimates, our model accurately predicted the measured ME gas composition, the kinetics of the MEE pressure response to a variety of conditions, and the counter-intuitive results of experiments and clinical observations. Other experiments showed that transmucosal exchange of inert gases is primarily perfusion limited, while that of gases that chemically bind with blood components is primarily diffusion limited. A corollary to these results is an increased transmucosal exchange of N2 and other inert gases by inflammation and/or greater blood flow rates. Representing persistent OME as a mucosal disease, the model prescribes the conditions under which maneuvers that artificially aerate the ME can promote disease resolution. The proposed experiments refine our mathematical model so as to better represent physiology, clarify certain aspects of normal ME physiology (e.g. role of mastoid air cells in pressure regulation), further define the effects of inflammation and effusion on the rate of transmucosal gas exchange, evaluate specific treatments for their effect on the rte of transmucosal gas exchange, complete the development and testing of treatments for their effect on the rate of transmucosal gas exchange, complete the development and testing of instruments that assess mucosal health, and generate initial estimates of the various model parameters for human subjects. These results will be used to. 1) improve our understanding of ME pressure regulation in health and disease, 2) develop diagnostic tests of ME pressure dysregulation, and 3) suggest rational interventions to present or treat OME.